Il-8 receptor antagonists

ABSTRACT

This invention relates to novel compounds of Formula (I) to (VII), and compositions thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

FIELD OF THE INVENTION

[0001] This invention relates to novel sulfonamide substituted diphenylurea compounds, pharmaceutical compositions, processes for theirpreparation, and use thereof in treating IL-8, GROα, GROβ, GROγ, NAP-2,and ENA-78 mediated diseases.

BACKGROUND OF THE INVENTION

[0002] Many different names have been applied to Interleukin-8 (IL-8),such as neutrophil attractant/activation protein-1 (NAP-1), monocytederived neutrophil chemotactic factor (MDNCF), neutrophil activatingfactor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 isa chemoattractant for neutrophils, basophils, and a subset of T-cells.It is produced by a majority of nucleated cells including macrophages,fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1α,IL-1β or LPS, and by neutrophils themselves when exposed to LPS orchemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest.84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J.Immunol. 144, 2223 (1990); Strieter, et al., Science 243, 1467 (1989)and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol.148, 3216 (1992).

[0003] GROβ, GROβ, GROγ and NAP-2 also belong to the chemokine family.Like IL-8 these chemokines have also been referred to by differentnames. For instance GROα, β, γ have been referred to as MGSAα, β and γrespectively (Melanoma Growth Stimulating Activity), see Richmond etal., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol148, 451 (1992). All of the chemokines of the α-family which possess theELR motif directly preceding the CXC motif bind to the IL-8 B receptor(CXCR2).

[0004] IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78 stimulate a number offunctions in vitro. They have all been shown to have chemoattractantproperties for neutrophils, while IL-8 and GROα have demonstratedT-lymphocytes, and basophilic chemotactic activity. In addition IL-8 caninduce histamine release from basophils from both normal and atopicindividuals. GRO-α and IL-8 can in addition, induce lysozomal enzymerelease and respiratory burst from neutrophils. IL-8 has also been shownto increase the surface expression of Mac-1 (CD11b/CD18) on neutrophilswithout de novo protein synthesis. This may contribute to increasedadhesion of the neutrophils to vascular endothelial cells. Many knowndiseases are characterized by massive neutrophil infiltration. As IL-8,GROα, GROβ, GROγ and NAP-2 promote the accumulation and activation ofneutrophils, these chemokines have been implicated in a wide range ofacute and chronic inflammatory disorders including psoriasis andrheumatoid arthritis, Baggiolini et al., FEBS Lett. 307, 97 (1992);Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al.,Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87,463 (1991); Miller et al., Am. Rev. Respir. Dis. 146,427 (1992); Donnelyet al., Lancet 341, 643 (1993). In addition the ELR chemokines (thosecontaining the amino acids ELR motif just prior to the CXC motif) havealso been implicated in angiostasis, Strieter et al., Science 258, 1798(1992).

[0005] In vitro, IL-8, GROα, GROβ, GROγ and NAP-2 induce neutrophilshape change, chemotaxis, granule release, and respiratory burst, bybinding to and activating receptors of the seven-transmembrane,G-protein-linked family, in particular by binding to IL-8 receptors,most notably the IL-8β receptor (CXCR2). Thomas et al., J. Biol. Chem.266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). Thedevelopment of non-peptide small molecule antagonists for members ofthis receptor family has precedent. For a review see R. Freidinger in:Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel1993. Hence, the IL-8 receptor represents a promising target for thedevelopment of novel anti-inflammatory agents.

[0006] Two high affinity human IL-8 receptors (77% homology) have beencharacterized: IL-8Rα, which binds only IL-8 with high affinity, andIL-8Rβ, which has high affinity for IL-8 as well as for GROα, GROβ, GROγand NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280(1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J.Biol. Chem. 267, 25402 (1992); and Gayle et al., J. Biol. Chem. 268,7283 (1993).

[0007] There remains a need for treatment, in this field, for compounds,which are capable of binding to the IL-8 α or β receptor. Therefore,conditions associated with an increase in IL-8 production (which isresponsible for chemotaxis of neutrophil and T-cells subsets into theinflammatory site) would benefit by compounds, which are inhibitors ofIL-8 receptor binding.

SUMMARY OF THE INVENTION

[0008] This invention provides for a method of treating a chemokinemediated disease, wherein the chemokine is one which binds to an IL-8 aor b receptor and which method comprises administering an effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof. In particular the chemokine is IL-8.

[0009] This invention also relates to a method of inhibiting the bindingof IL-8 to its receptors in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

[0010] The present invention also provides for the novel compounds ofFormula (I), and pharmaceutical compositions comprising a compound ofFormula (I), and a pharmaceutical carrier or diluent.

[0011] Compounds of Formula (I) useful in the present invention arerepresented by the structure:

[0012] wherein

[0013] R_(b) is independently selected from the group consisting ofhydrogen, NR₆R₇, OH, OR_(a), C₁₋₅alkyl, aryl, arylC₁₋₄alkyl, arylC₂₋₄alkenyl, cycloalkyl, cycloalkyl C₁₋₅ alkyl, heteroaryl,heteroarylC₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, heterocyclicC₁₋₄alkyl, and a heterocyclic C₂₋₄alkenyl moiety, all of which moietiesmay be optionally substituted one to three times independently by asubstituent selected from the group consisting of halogen, nitro,halosubstituted C₁₋₄ alkyl, C₁₋₄ alkyl, amino, mono or di-C₁₋₄ alkylsubstituted amine, OR_(a),C(O)R_(a),NR_(a)C(O)OR_(a), OC(O)NR₆R₇,hydroxy, NR₉C(O)R_(a), S(O)_(m)′R_(a), C(O)NR₆R₇, C(O)OH, C(O)OR_(a),S(O)₂NR₆R₇ and NHS(O)₂R_(a); or the two R_(b) substituents join to forma 3-10 membered ring, optionally substituted and containing, in additionto carbon, independently, 1 to 3 optionally substituted moietiesselected from the group consisting of NR_(a), O, S, SO, and SO₂; R_(a)is selected from the group consisting of alkyl, aryl, arylC₁₋₄alkyl,heteroaryl, heteroaryl C₁₋₄alkyl, heterocyclic, COOR_(a), and aheterocyclic C₁₋₄alkyl moiety, all of which moieties may be optionallysubstituted;

[0014] m is an integer having a value of 1 to 3;

[0015] m′ is 0, or an integer having a value of 1 or 2;

[0016] n is an integer having a value of 1 to 3;

[0017] q is 0, or an integer having a value of 1 to 10;

[0018] t is 0, or an integer having a value of 1 or 2;

[0019] s is an integer having a value of 1 to 3;

[0020] R₁ is independently selected from the group consisting ofhydrogen, halogen, nitro, cyano, C₁₋₁₀ alkyl, halosubstituted C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy, halosubstituted C₁₋₁₀alkoxy, azide,S(O)_(t)R₄, (CR₈R₈)_(q)S(O)_(t)R₄, hydroxy, hydroxy substitutedC₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryl C₂₋₁₀ alkenyl, aryloxy, aryl C₁₋₄alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C₂₋₁₀ alkenyl,heteroaryl C₁₋₄ alkyloxy, heterocyclic, heterocyclic C₁₋₄alkyl,heterocyclicC₁₋₄alkyloxy, heterocyclicC₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅,(CR₈R₈)_(q)C(O)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅, (CR₈R₉)_(q)C(O)NR₄R₁₀,S(O)₃R₈, (CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenylC(O)OR₁₁, (CR₈R₈)_(q)C(O)OR₁₁, (CR₈R₈)_(q) OC(O)R₁₁, (CR₈R₈)qNR₄C(O)R₁₁,(CR₈R₈)_(q) C(NR₄)NR₄R₅, (CR₈R₈)_(q) NR₄C(NR₅)R₁₁, (CR₈R₈)_(q)NHS(O)₂R₁₃, and (CR₈R₈)_(q) S(O)₂NR₄R₅; or two R₁ moieties together mayform O—(CH₂)_(s)O or a 5 to 6 membered saturated or unsaturated ring,such that the alkyl, aryl, arylalkyl, heteroaryl, or heterocyclicmoieties may be optionally substituted;

[0021] R₄ and R₅ are independently selected form the group consisting ofhydrogen, optionally substituted C₁₋₄ alkyl, optionally substitutedaryl, optionally substituted aryl C₁₋₄alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl C₁₋₄alkyl, heterocyclic,and heterocyclicC₁₋₄ alkyl, or R₄ and R₅ together with the nitrogen towhich they are attached form a 5 to 7 member ring which may optionallycomprise an additional heteroatom selected from O, N and S;

[0022] R₆ and R₇ are independently selected from the group consisting ofhydrogen, a C₁₋₄ alkyl, heteroaryl, aryl, aklyl aryl, and alkyl C₁₋₄heteroalkyl; or R₆ and R₇ together with the nitrogen to which they areattached form a 5 to 7 member ring which ring may optionally contain anadditional heteroatom which is selected from the group consisting ofoxygen, nitrogen or sulfur, and which ring may be optionallysubstituted;

[0023] Y is selected from the group consisting of furan, thiophene,pyrrole, oxazole, imidazole, thiazole, pyrazole, isooxazole,isothiazole, 1,2,3 or 1,2,4 oxadiazole, 1,2,3 or 1,2,4 triazole, 1,2,3or 1,2,4 thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, 1,3,5,or 1,2,3 or 1,2,4 triazine, 1,2,4,5 tetrazine, indole, benzofuran,indazole, benzimidazole, benzothiazole, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline and quinoxaline all of whichmoeities can be substituted 1-3 times with R₁

[0024] R₈ is hydrogen or C₁₋₄ alkyl;

[0025] R₉ is hydrogen or a C₁₋₄ alkyl;

[0026] R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈;

[0027] R₁₁ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₄ alkyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₄alkyl, optionally substituted heteroaryl,optionally substituted heteroarylC₁₋₄alkyl, optionally substitutedheterocyclic, and optionally substituted heterocyclicC₁₋₄alkyl; and

[0028] R₁₃ is selected from the group consisting of C₁₋₄ alkyl, aryl,aryl C_(1∝)alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclic, andheterocyclicC₁₋₄alkyl;

[0029] or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The compounds of Formula (I), may also be used in associationwith the veterinary treatment of mammals, other than humans, in need ofinhibition of IL-8 or other chemokines which bind to the IL-8 α and βreceptors. Chemokine mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedherein in the Methods of Treatment section.

[0031] Suitably, R_(b) is independently hydrogen, NR₆R₇, OH, OR_(a),C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, aryl C₂₋₄alkenyl, heteroaryl,heteroarylC₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, heterocyclicC₁₋₄alkyl, or a heterocyclic C₂₋₄alkenyl moiety, all of which moietiesmay be optionally substituted one to three times independently byhalogen, nitro, halosubstituted C₁₋₄ alkyl, C₁₋₄ alkyl, amino, mono ordi-C₁₋₄ alkyl substituted amine, cycloalkyl, cycloalkyl C₁₋₅ alkyl,OR_(a), C(O)R_(a), NR_(a)C(O)OR_(a), OC(O)NR₆R₇, aryloxy, aryl C₁₋₄ oxy,hydroxy, C₁₋₄ alkoxy, NR₉C(O)R_(a), S(O)_(m′)R_(a), C(O)NR₆R₇, C(O)OH,C(O)OR_(a), S(O)₂NR₆R₇, NHS(O)₂R_(a). Alternatively, the two R_(b)substituents can join to form a 3-10 membered ring, optionallysubstituted and containing, in addition to carbon, independently, 1 to 3NR₉, O, S, SO, or SO₂ moities which can be optionally substituted.

[0032] Suitably, R_(a) is an alkyl, aryl, arylC₁₋₄alkyl, heteroaryl,heteroaryl C₁₋₄alkyl, heterocyclic, or a heterocyclic C₁₋₄alkyl moiety,all of which moieties may be optionally substituted.

[0033] Suitably, R₁ is independently selected from hydrogen; halogen;nitro; cyano; halosubstituted C₁₋₁₀ alkyl, such as CF₃, C₁₋₁₀ alkyl,such as methyl, ethyl, isopropyl, or n-propyl, C₂₋₁₀ alkenyl, C₁₋₁₀alkoxy, such as methoxy, or ethoxy; halosubstituted C₁₋₁₀ alkoxy, suchas trifluoromethoxy, azide, (CR₈R₈)_(q) S(O)_(t)R₄, wherein t is 0, 1 or2, hydroxy, hydroxy C₁₋₄alkyl, such as methanol or ethanol, aryl, suchas phenyl or naphthyl, aryl C₁₋₄ alkyl, such as benzyl, aryloxy, such asphenoxy, aryl C₁₋₄ alkyloxy, such as benzyloxy; heteroaryl,heteroarylalkyl, heteroaryl C₁₋₄ alyloxy; aryl C₂₋₁₀ alkenyl, heteroarylC₂₋₁₀ alkenyl, heterocyclic C₂₋₁₀ alkenyl, (CR₈R₈)_(q)NR₄R₅, C₂₋₁₀alkenyl C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₁₀, S(O)₃H,S(O)₃R₈, (CR₈R₈)_(q)C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenylC(O)OR₁₁, (CR₈R₈)_(q) C(O)R₁₁, (CR₈R₈)_(q)C(O)OR₁₁, (CR₈R₈)_(q)OC(O)R₁₁, (CR₈R₈)_(q)NR₄C(O)R₁₁, (CR₈R₈)_(q)C(NR₄)NR₄R₅, (CR₈R₈)_(q)NR₄C(NR₅)R₁₁, (CR₈R₈)_(q)NHS(O)₂R₁₃, (CR₈R₈)_(q)S(O)₂NR₄R₅. All of thearyl, heteroaryl, and heterocyclic-containing moieties may be optionallysubstituted as defined herein below.

[0034] For use herein the term “the aryl, heteroaryl, and heterocycliccontaining moieties” refers to both the ring and the alkyl, or ifincluded, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenylrings. The term “moieties” and “rings” may be interchangeably usedthroughout.

[0035] Suitably, R₄ and R₅ are independently hydrogen, optionallysubstituted C₁₋₄ allyl, optionally substituted aryl, optionallysubstituted aryl C₁₋₄alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl C₁₋₄alkyl, heterocyclic,heterocyclicC₁₋₄ alkyl, or R₄ and R₅ together with the nitrogen to whichthey are attached form a 5 to 7 member ring which may optionallycomprise an additional heteroatom selected from O, N and S.

[0036] Suitably, R₈ is independently hydrogen or C₁₋₄ alkyl.

[0037] Suitably, R₉ is hydrogen or a C₁₋₄ alkyl;

[0038] Suitably, q is 0 or an integer having a value of 1 to 10.

[0039] Suitably, R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈, such as CH₂C(O)₂H orCH₂C(O)₂CH₃.

[0040] Suitably, R₁₁ is hydrogen, C₁₋₄ alkyl, aryl, aryl C₁₋₄ alkyl,heteroaryl, heteroaryl C₁₋₄alyl, heterocyclic, or heterocyclicC₁₋₄alkyl.

[0041] Suitably, R₁₂ is hydrogen, C₁₋₁₀ alkyl, optionally substitutedaryl or optionally substituted arylalkyl.

[0042] Suitably, R₁₃ is C₁₋₄alkyl, aryl, arylalkyl, heteroaryl,heteroarylC₁₋₄alkyl, heterocyclic, or heterocyclicC₁₋₄alkyl, wherein allof the aryl, heteroaryl and heterocyclic containing moieties may all beoptionally substituted.

[0043] Suitably, Y is is furan, thiophene, pyrrole, oxazole, imidazole,thiazole, pyrazole, isooxazole, isothiazole, 1,2,3 or 1,2,4 oxadiazole,1,2,3 or 1,2,4 triazole, 1,2,3 or 1,2,4 thiadiazole, pyridine,pyrimidine, pyridazine, pyrazine, 1,3,5, or 1,2,3 or 1,2,4 triazine,1,2,4,5 tetrazine, indole, benzofuran, indazole, benzimidazole,benzothiazole, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline and quinoxaline all of which moeities can be substituted 1-3times with R₁; C₂₋₁₀ alkenyl C(O)OR₁₁; (CR₈R₈)_(q) C(O)OR₁₂; (CR₈R₈)_(q)OC(O) R₁₁; (CR₈R₈)_(q)C(NR₄)NR₄R₅; (CR₈R₈)_(q) NR₄C(NR₅)R₁₁; (CR₈R₈)_(q)NR₄C(O)R₁₁; (CR₈R₈)_(q) NHS(O)₂R₁₃; or (CR₈R₈)_(q) S(O)₂NR₄R₅; or two Ymoieties together may form O—(CH₂)_(s)—O or a 5 to 6 membered saturatedor unsaturated ring. The aryl, heteroaryl and heterocyclic containingmoieties noted above may all be optionally substituted as definedherein.

[0044] Suitably s is an integer having a value of 1 to 3.

[0045] Suitably, R_(a) is an alkyl, aryl C₁₋₄ alkyl, heteroaryl,heteroaryl-C₁₋₄alkyl, heterocyclic, or a heterocyclicC₁₋₄ alkyl, whereinall of these moieties may all be optionally substituted.

[0046] As used herein, “optionally substituted” unless specificallydefined shall mean such groups as halogen, such as fluorine, chlorine,bromine or iodine, hydroxy; hydroxy substituted C₁₋₁₀alkyl, C₁₋₁₀alkoxy, such as methoxy or ethoxy, S(O)_(m′)C₁₋₁₀ alkyl, wherein m′ is0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl;amino, mono & di-substituted amino, such as in the NR₄R₅ group,NHC(O)R₄, C(O)NR₄R₅, C(O)OH, S(O)₂NR₄R₅, NHS(O)₂R₂₀, C₁₋₁₀ alkyl, suchas methyl, ethyl, propyl, isopropyl, or t-butyl, halosubstituted C₁₋₁₀alkyl, such CF₃, an optionally substituted aryl, such as phenyl, or anoptionally substituted arylalkyl, such as benzyl or phenethyl,optionally substituted heterocylic, optionally substitutedheterocyclicaiLyl, optionally substituted heteroaryl, optionallysubstituted heteroaryl alkyl, wherein these aryl, heteroaryl, orheterocyclic moieties may be substituted one to two times by halogen;hydroxy; hydroxy substituted alkyl, C₁₋₁₀ alkoxy; S(O)_(m′)C₁₋₁₀ alkyl;amino, mono & di-substituted alkyl amino, such as in the NR₄R₅ group;C₁₋₁₀ alkyl, or halosubstituted C₁₋₁₀ alkyl, such as CF₃.

[0047] R₂₀ is suitably C₁₋₄ alkyl, aryl, aryl C₁₋₄alkyl, heteroaryl,heteroarylC₁₋₄alkyl, heterocyclic, or heterocyclicC₁₋₄alkyl.

[0048] Suitable pharmaceutically acceptable salts are well known tothose skilled in the art and include basic salts of inorganic andorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid,acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalicacid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylicacid, phenylacetic acid and mandelic acid. In addition, pharmaceuticallyacceptable salts of compounds of Formula (I) may also be formed with apharmaceutically acceptable cation. Suitable pharmaceutically acceptablecations are well known to those skilled in the art and include alkaline,alkaline earth, ammonium and quaternary ammonium cations.

[0049] The following terms, as used herein, refer to:

[0050] “halo”—all halogens, that is chloro, fluoro, bromo and iodo.

[0051] “C₁₋₁₀alkyl” or “alkyl”—both straight and branched chain moietiesof 1 to 10 carbon atoms, unless the chain length is otherwise limited,including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

[0052] “cycloalkyl” is used herein to mean cyclic moiety, preferably of3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl,cyclohexyl, and the like.

[0053] “alkenyl” is used herein at all occurrences to mean straight orbranched chain moiety of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

[0054] “aryl”—phenyl and naphthyl;

[0055] “heteroaryl” (on its own or in any combination, such as“heteroaryloxy”, or “heteroaryl alkyl”)—a 5-10 membered aromatic ringsystem in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O or S, such as, but notlimited, to pyrrole, pyrazole, furan, thiophene, quinoline,isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole,thiazole, thiadiazole, triazole, imidazole, or benzimidazole.

[0056] “heterocyclic” (on its own or in any combination, such as“heterocyclicalkyl”)—a saturated or partially unsaturated 4-10 memberedring system in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O, or S; such as, but notlimited to, pyrrolidine, piperidine, piperazine, morpholine,tetrahydropyran, thiomorpholine, or imidazolidine. Furthermore, sulfurmay be optionally oxidized to the sulfone or the sulfoxide.

[0057] “arylalkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean C₁₋₁₀ alkyl, as defined above, attached to an aryl,heteroaryl or heterocyclic moiety, as also defined herein, unlessotherwise indicated.

[0058] “sulfinyl”—the oxide S (O) of the corresponding sulfide, the term“thio” refers to the sulfide, and the term “sulfonyl” refers to thefully oxidized S(O)₂ moiety.

[0059] “wherein two R₁ moieties may together form a 5 or 6 memberedsaturated or unsaturated ring” is used herein to mean the formation ofan aromatic ring system, such as naphthalene, or is a phenyl moietyhaving attached a 6 membered partially saturated or unsaturated ringsuch as a C₆ cycloalkenyl, i.e. hexene, or a C₅ cycloalkenyl moiety,such as cyclopentene.

[0060] Illustrative compounds of Formula (I) include:

[0061]N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(pyridin-2-yl)urea;

[0062]N-(3-aminosulfonyl4-chloro-2-hydroxyphenyl)-N′-(2-chloro-pyridin-3-yl)urea;

[0063]N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1-phenyl-1H-1,2,3-triazol-5-yl)urea;

[0064]N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1,3-dimethylpyrazol-5-yl)urea;

[0065]N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1-methylpyrazol-5-yl)urea;and

[0066]N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-methyl-pyridin-3-yl)urea.

[0067]N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(3,5-dimethylisoxazol4-yl)urea;

[0068]N-(3-aminosulfonylAchloro-2-hydroxyphenyl)-N′-(1-N-oxide-pyridin-3-yl)urea;

[0069]N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-choro-1-N-oxide-pyridin-3-yl)urea;

[0070]N-(3-aminosulfonyl4-chloro-2-hydroxyphenyl)-N′-(3-benzyloxythieno[2,3-b]pyridin-2-yl)urea;

[0071]N-(3-aminosulfonylamino-2-hydroxyphenyl)-N′-(3-methyhsoxazol-4yl)urea;and

[0072]N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(5-methylisoxazol4-yl)urea.

METHODS OF PREPARATION

[0073] The compounds of Formula (I) may be obtained by applyingsynthetic procedures, some of which are illustrated in the Schemesbelow. The synthesis provided for in these Schemes is applicable for theproducing compounds of Formulas (I) having a variety of different R, R₁,and Z groups which are reacted, employing optional substituents whichare suitably protected, to achieve compatibility with the reactionsoutlined herein. Subsequent deprotection, in those cases, then affordscompounds of the nature generally disclosed. Once the urea nucleus hasbeen established, further compounds of these formulas may be prepared byapplying standard techniques for functional group interconversion, wellknown in the art.

[0074] a)i)NCS, AcOH, H₂O ii)NaOH MeOH b)H₂SO₄, HNO₃ c) NaOH MeOH d)PCl₅, POCl₃ e) NHR′R″, Et₃N, CH₂Cl₂

[0075] The route to the 2,4 dichloro sulfonamide 5-scheme 1 is outlinedabove, wherein the commercially available 2,6-dichloro thiol can beoxidized to the sulfonyl halide using a halogenating agent such as NCS,NBS, chlorine or bromine in the presence of a protic solvent such asalcohol, acetic acid or water. The sulfonyl halide can be hydrolyzed byusing a metal hydroxide such as sodium or potassium hydroxide to formthe corresponding sulfonic acid salt. The sulfonic acid salt can then benitrated under nitration conditions such as nitric acid in a solvent ofstrong acid such as sulfuric acid to form the nitro phenyl sulfonic acid3-scheme 1. The sulfonic acid 3-scheme 1 can be converted to thesulfonamide 5-scheme 1 using a three step procedure involving theformation of the metal salt using a base such as sodium hydroxide,sodium hydride or sodium carbonate to form 4-scheme 1. The sulfonic acidsalt is then converted to the sulfonyl chloride using PCl₅ with POCl₃ asa solvent. The sulfonyl chloride can then be converted to thecorresponding sulfonamide using the desired amine HNR′R″ in a non-proticsolvent such as CH₂Cl₂ using a base such as triethyl amine attemperatures ranging from −78 ° C. to 60° C. to form the correspondingsulfonamide 5-scheme 3. This method is not limited to the2,6-dichlorophenyl thiol it can also be applied to the2,6-difluorophenyl thiol, 2,6-dibromophenyl thiol and the2,6-diiodophenyl thiol. The halogens in these compounds can be convertedto the corresponding cyano, amino, thiol, or alkoxy compounds bynucleophilic displacement reactions using nucleophiles such as alkylthiolates, alkoxides, amine and cyanides. The halogens can also befurther functionalized by palladium coupling and carbonylationreactions, well known in the art, to form the corresponding amido,carbonyl, alkenyl, alkyl, phenyl and heterocycic substituted products asrequired by Formula (I).

[0076] The ortho chloride can be selectively hydrolyzed by using ahydroxide base in a protic or non protic solvent or by in situgeneration of hydroxide by the use of NaH and water in a non proticsolvent such as THF to form 2-scheme 2. The nitro can then be reducedusing a number of reduced agents such as palladium on carbon andhydrogen, tin chloride, iron, rhodium or sodium sulfite to form thedesired aniline 3-scheme 2.

[0077] a) NaH, H₂O, THF b)Pd/C, H₂, EtOAc

[0078] If the desired hydroxyaniline 3 in Scheme 2 is not commerciallyavailable, it can be prepared as outlined in Scheme 3. Commerciallyavailable substituted 3-chloroanilines 1 can be converted to the amide 2using standard conditions well known in the art such as pivavolylchloride and triethylamine in a suitable organic solvent such asmethylene chloride. The amide 2 can be converted to the benzoxazole 3using an excess amount of a strong base such as butyllithium in asuitable organic solvent such as THF under reduced reaction temperatures(−20 to −40° C.) followed by quenching the reaction with sulfur dioxidegas. The sulfonic acid 3 can be converted to the sulfonamide 4 using viathe intermediate sulfurylchloride. The sulfonyl chloride can be obtainedfrom the sulfonic acid 3 using standard conditions well known in the artsuch as sulfuryl chloride in a suitable organic solvent such asmethylene chloride. The sulfonyl chloride intermediate can betransformed to the sulfonamide 4 using standard conditons well known inthe art by reacting it with the amine HN(R_(b))₂ in the presence of asuitable amine base such as triethylamine in a suitable organic solventsuch as methylene chloride. The desired phenolaniline 5 can be obtainedfrom the benzoxazole 4 using standard hydrolysis conditions well knownin the art such as sulfuric acid in water and heating at 85° C.

[0079] a) PivCl, TEA; b) i. n-BuLi (2 eq.), −40° C., THF, ii. SO₂; c) i.SO₂Cl₂, ii. HN(R_(b))₂, TEA; d) H₂SO₄, H₂O

[0080] The urea can be formed by coupling the heterocyclic isocyanatewith desired hydroxyaniline. If the desired heterocyclic isocyanate isunstable like the 2-pyridyl isocyanate, the isocyanate is generated inthe presence of hydroaniline by premixing the acylazide with hydroxyaniline and trapping the heterocyclic isocyanate in situ. The acyl azidecan be generated by treating the carboxy heterocycle with D)PPA or by atwo step procedure involving formation of the acid halide or mixedanhydride followed by attack with an azide salt such as sodium azide. Ifthe isocyanate is stable then the isocyanate can be formed by reactionof the corresponding heterocyclic amine with triphosgene.

[0081] a) EtOCOCl, Et₃N, acetone/water b) NaN₃ c) DMF

[0082] Alternatively the isocyanate can be formed on the other side ofthe urea by first protecting the hydroxyl using a standard protectinggroup such as TBS to form 2 scheme 5. The protected hydroxy aniline isthen converted to the isocyanate using standard conditions such astreatment with triphosgene in the presence of a base such as triethylamine or sodium bicarbonate to form 3 scheme 5. The isocyanate is thencoupled with heterocyclic amine to form the corresponding urea followedby deprotection of the phenol group using standard procedures to formthe desired compound 4 scheme 5.

[0083] a)TBSCl, imid, CH₂Cl₂ b)triphosgene, Et₃N, CH₂Cl₂ c)DMF d)TBAF,CH₂Cl₂

SYNTHETIC EXAMPLES

[0084] The invention will now be described by reference to the followingexamples, which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand all reactions run under anhydrous conditions in an argon atmosphereunless otherwise indicated.

[0085] In the Examples, all temperatures are in degrees Centigrade (°C.). Mass spectra were performed upon a VG Zab mass spectrometer usingfast atom bombardment, unless otherwise indicated. ¹H-NMR (hereinafter“NMR”) spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400spectrometer. Multiplicities indicated are: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat.indicates a saturated solution, eq indicates the proportion of a molarequivalent of reagent relative to the principal reactant.

[0086] General Method:

[0087] Synthesis of 3-(aminosulfonyl)4-chloro-2-hydroxy aniline.

[0088] a) 2,6-Dichlorobenzenesulfonyl chloride

[0089] Into a mixture of 200 milliliters (hereinafter “mL”) of aceticacid, water and dichloromethane (3/1/4, v/v/v), 2,6-dichlorobenzenethiol(10.0 grams (hereinafter “g”), 55.8 millimoles (hereinafter “mmol”),N-chlorosuccinimide (37.28 g, 279 mmol) and potassium acetate (2.29 g,27.9 mmol) were added. The resulting mixture was stirred at 0° C., thenwarmed to room temperature overnight. The mixture was then diluted with200 mL of dichloromethane, and washed with water (100 mL×3). The organiclayer was dried (NaSO₄) and concentrated to give the desired product (11g, 80%). ¹H NMR (CDCl₃): δ 7.57 (d, 2H), 7.47 (t,1H).2,6-Dichloro-3-nitrobenzenesulfonic acid. Lithium hydroxide hydrate(12.64 g, 0.301 mol) was added to a solution of2,6-dichlorobenzenesulfonyl chloride (35.53 g, 0.146 mol) in MeOH (600mL) and the reaction was allowed to stir at room temperature for 3 hr.The reaction mixture was filtered to remove suspended solids and thenconcentrated. The resulting solid was dried in vacu overnight to removeany residual MeOH. The solid was then dissolved in H₂SO₄ (300 mL) andchilled in an ice bath. A solution of H₂SO₄ (35 mL) and HNO₃ (13.2 mL)was slowly added to the above reaction over 90 min. The reaction wasallowed to warm up to room temperature overnight and then slowly pouredinto ice water (1200 mL) and extracted with EtOAc. The combined organiclayers were dried (MgSO₄) and concentrated to yield2,6-dichloro-3-nitrobenzenesulfonic acid (44.35 g, 99%) as thedihydrate. EI-MS (m/z) 270 (M−H)⁻.

[0090] b) 2,6-Dichloro-3-nitrobenzenesulfonyl chloride

[0091] Potassium hydroxide (12.07 g, 0.215 mol) was added to a solutionof 2,6-dichloro-3-nitrobenzenesulfonic acid dihydrate (44.35 g, 0.144mol) in MeOH (850 mL) and the reaction was allowed to stir at roomtemperature for 14 hr. The reaction mixture was concentrated and theresulting solid was dried in vacu overnight. To this was added PCl₅(30.00 g, 0.144 mol) followed by POCl₃ (475 mL) and the mixture wasrefluxed overnight. The reaction was then cooled to room temperature andconcentrated. The resulting mixture was taken up in EtOAc and chilled inan ice bath. Ice chunks were slowly added to the reaction mixture toquench any leftover PCl₅. When bubbling ceased, water was added and thereaction mix was extracted with EtOAc. The organic layer was dried(MgSO₄) and concentrated to yield 2,6-Dichloro-3-nitrobenzenesulfonylchloride (40.42 g, 97%). ¹H NMR (DMSO-d₆), 7.88 (d, 1H), 7.75 (d, 1H).

[0092] c) 2,6-dichloro-3-nitrobenzenesulfonamide

[0093] Into a solution of 2,6-dichloro-3-nitrobenzenesulfonyl chloride(9.48 g, 32.6 mmol) in 105 mL of dichloromethane at −78° C. was bulbedamonia gas for 6 hours. The mixture was warmed to room temperature andacidified to pH >1 with 6N aq. HCl, then extracted with ethyl acetate.The combined organic layer was then concentrated to give the crudematerial. Column chromatography on silica gel, eluting with ethylacetate/hexane (50/50, v/v/), gave the desired product (6.30 g, 71%). ¹HNMR (DMSO-d₆): δ 8.26 (s, 2H), 8.20 (d, 1H), 7.92 (d, 1H).

[0094] d) 6-chloro-2-hydroxy-3-nitrobenzenesulfonamide

[0095] A mixture of 2,6-dichloro-3-nitrobenzenesulfonamide (2.61 g, 9.64mmol), 60% sodium hydride (1.15 g, 28.9 mmol) and water (174 μL, 9.64mmol) was heated to 45° C. while kept at argon atmosphere for 3 days.The reaction was monitored by ¹H NMR. 0.1 equivalent water was added tothe mixture when the reaction was not completed. The solvent wasevaporated when the reaction almost completed indicated by ¹H NMR. Theresidue was diluted with ethyl acetate and washed with 1N aq. HCl. Thesolvent was concentrated to give the crude material. Columnchromatography on silica gel, eluting with ethyl acetate/hexane/aceticacid (50/48/2, v/v/v), gave the desired product (1.87 g, 77%). EI-MS(m/z)250.84, 252.89 (M⁻).

[0096] e) 3-amino-6-chloro-2-hydroxybenzenesulfonamide

[0097] To a solution of 6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (3g, 11.9 mmol) in ethyl acetate, was added 10% Pd/C (1.24 g). The mixturewas flushed with argon, and then stirred on Parr apparatus at 40 psi for25 min at room temperature. The mixture was filtered through celite andthe celite was washed with methanol. The solvent was evaporated to givethe desired product (2.51 g, 95%). EI-MS (m/z) 222.75, 224.74 (M⁻).

[0098] f) N-(3,4-Dichloro-phenyl)-2,2-dimethyl-propionamide

[0099] 3,4-dichloroaniline (150 g) in TBME (1L) was cooled to 10-15 ° C.30% aq NaOH (141 g, 1.14 equiv) was added, and the solution stirredvigorously via overhead mechanical stirrer. Trimethylacetyl chloride(“PivCl”, 126 mL) was added at such a rate as to keep the internaltemperature below 30° C. During this addition, the solution mixturebecomes thick with white solid product. When the addition was complete(10-15 min), the mixture was heated to 30-35° C. for 1 hr, and thenallowed to cool. The reaction mixture was held at −5 ° C. (overnight),and then filtered, rinsing first with 90:10 water/MeOH (600 mL) and thenwater (900 mL). Drying under vacuum yielded 195 g (86%) product, asoff-white crystals. LCMS m/z 246(M−H)⁺.

[0100] g) 2-tert-Butyl-6-chloro-benzooxazole-7-sulfonyl chloride

[0101] The solution of N-(3,4-dichloro-phenyl)-2,2-dimethyl-propionamide(10 g, 41 mmol) in dry THF (100 mL) was cooled to −72 ° C. under argon.n-Butyl lithium (1.6M in hexane, 64 mL, 102 mmol) was added dropwise.The solution warmed to ca. −50° C. over 45 minutes, and then was kept inthe −25-−10 ° C. range for 2 hrs. The solution was then recooled to −78°C., and sulfur dioxide was bubbled through the solution for 30 min. Thesolution was then allowed to warm to room temperature for 2 h, and a Arstream was bubbled through the solution, with a gas outlet provided sothat any excess sulfur dioxide could escape during the warming. The THFsolution was cooled in an ice bath, and sulfuryl chloride (3.58 mL, 44.9mmol) was added dropwise. After a few minutes, the solution was warmedto room temperature for overnight. The mixture was concentrated, dilutedwith ethyl acetate and washed with water. Decolorizing carbon was addedand the mixture was filtered. The resulting solution was dried (sodiumsulfate), filtered and concentrated to afford the title compound (12.4g, 98%). ¹H NMR (CDCl₃)·7.92 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=8.4 Hz),1.57 (s, 9H). General procedure for the hydrolysis of the benzooxazoleto the desired aniline.

[0102] To a solution of2-tert-Butyl-6-chloro-7-(aminosulfonyl)-benzooxazole in 1,4-dioxane (20mL) was treated with water (4 mL) and conc. H₂SO₄ (4 mL). The mixturewas heated to 85° C. for 14 h. The reaction was cooled to roomtemperature, and then basified to pH=14 with 25% aq NaOH. washed. Themixture was extracted with ethyl acetate (3 times), dried with MgSO₄,filtered, and concentrated to afford the title compound.

Example 1 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(pyridin-2-yl)urea

[0103] a) 2-(azidocarbonyl)-pyridine

[0104] To a solution of picolinic acid (1.0 g, 8.12 mmol) in a mixtureof acetone (10 mL) and water (3 mL) was added triethylamine (1.7 mL,12.2 mmol). The mixture was cooled to 0° C. in a ice-bath.Ethylchloroformate (1.32 g, 12.2 mmol) was then added and the resultingmixture was stirred for 1.5 hours at 0° C. To the mixture was addedsodium azide (0.844 g, 13.0 mmol), and the mixture was stirred foranother 1.5 hours. The mixture was concentrated, the residue was dilutedwith dichloromethane and washed with water. The organic layer was driedover MgSO₄ and concentrated to give desired product (817 mg, 68%). ¹HNMR(CDCl₃) (δ) 8.74 (d, 1H), 8.15 (d, 1H), 7.88 (m, 1H), 7.55 (m, 1H).

[0105] b)N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(pyridin-2-yl)urea

[0106] Under Argon, a solution of3-amino-6-chloro-2-hydroxybenzenesulfonamide (300 mg, 1.35 mmol) and2-(azidocarbonyl)-pyridine (400 mg, 2.70 mmol) in 5 mL ofN,N-dimethyl-formamide was heated to 80° C. for 2 hours. The mixture waskept at room temperature for another 20 hours. Purification upon GilsonHPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10min), gave the desired product (287 mg, 62%). LC-MS (m/z) 343.0 (M⁺).

Example 2 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-chloro-pyridin-3-yl)urea

[0107] a) 3-(azidocarbonyl)-2-chloropyridine

[0108] To a solution of 2-chloronicotinic acid (1.0 g, 6.35 mmol) in amixture of acetone (14 mL) and water (6 mL) was added triethylamine(0.97 mL, 6.98 mmol). The mixture was cooled to 0° C. in a ice-bath.Ethylchloroformate (1.03 g, 9.5 mmol) was then added and the resultingmixture was stirred for 1.0 hour at 0° C. To the mixture was addedsodium azide (0.70 g, 10.8 mmol), and the mixture was stirred foranother 3 hours. The mixture was concentrated, the residue was dilutedwith dichloromethane and washed with water. The organic layer was driedover MgSO₄ and concentrated to give desired product (550 mg, 48%). ¹HNMR(CDCl₃) (δ) 8.57 (d, 1H), 8.22 (d, 1H), 7.37 (t, 1H).

[0109] b)N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-chloro-pyridin-3-yl)urea

[0110] Under Ar, a solution of3-amino-6-chloro-2-hydroxybenzenesulfonamide (50 mg, 0.22 mmol) and3-(azidocarbonyl)-2-chloropyridine (123 mg, 0.67 mmol) in 1 mL ofN,N-dimethyl-formamide was stirred at room temperature for 3 days.Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90,v/v to 90/10, v/v, over 10 min), gave the desired product (15 mg, 18%).LC-MS (m/z) 377.0 (M⁺).

Example 3 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1-phenyl-1H-1,2,3-triazol-5-yl)urea

[0111] a) 5-(azidocarbonyl)-1-phenyl-1H-1,2,3-triazole

[0112] To a solution of 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid(500 mg, 2.64 mmol) in a mixture of acetone (10 mL) and water (5 mL) wasadded triethylamine (0.55 mL, 3.96 mmol). The mixture was cooled to 0°C. in a ice-bath. Ethylchloroformate (573 mg, 5.28 mmol) was then addedand the resulting mixture was stirred for 1.5 hours at 0° C. To themixture was added sodium azide (0.844 g, 13.0 mmol), and the mixture wasstirred for another 1.5 hours. The mixture was concentrated, the residuewas diluted with dichloromethane and washed with water. The organiclayer was dried over MgSO₄ and concentrated to give desired product (100mg, 18%). ¹HNMR (CDCl₃) (δ) 8.30 (s, 1H), 7.57 (t, 3H), 7.51 (d, 2H).

[0113] b)N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1-phenyl-1H-1,2,3-triazol-5-yl)urea

[0114] Under Ar, a solution of3-amino-6-chloro-2-hydroxybenzenesulfonamide (104 mg, 0.46 mmol) and5-(azidocarbonyl)-1-phenyl-1H-1,2,3-triazole (100 mg, 0.46 mmol) in 5 mLof N,N-dimethyl-formamide was stirred at room temperature for 3 days.Purification upon Gilson HPLC twice, eluting with acetonitrile/water(10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (2.7mg, 1.4%). LC-MS (m/z) 409.9 (M⁺).

Example 4 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1,3-dimethylpyrazol-5-yl)urea

[0115] a) 5-(azidocarbonyl)-1,3-dimethylpyrazole

[0116] To a solution of 1,3-dimethylpyrazol-5-carboxylic acid (500 mg,3.57 mmol) in a mixture of acetone (10 mL) and water (5 mL) was addedtriethylamine (0.75 mL, 7.13 mmol). The mixture was cooled to 0° C. in aice-bath. Ethylchloroformate (774 mg, 7.13 mmol) was then added and theresulting mixture was stirred for 1.5 hours at 0° C. To the mixture wasadded sodium azide (0.844 g, 13.0 mmol), and the mixture was stirred foranother 1.5 hours. The mixture was concentrated, the residue was dilutedwith dichloromethane and washed with water. The organic layer was driedover MgSO₄ and concentrated to give desired product (203 mg, 34%). ¹HNMR(CDCl₃) (δ) 6.60 (s, 1H), 4.11 (s, 3H), 2.25 (s, 3H).

[0117] b)N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1,3-dimethylpyrazol-5-yl)urea

[0118] Under Ar, a solution of3-amino-6-chloro-2-hydroxybenzenesulfonamide (137 mg, 0.61 mmol) and5-(azidocarbonyl)-1,3-dimethylpyrazole (203 mg, 1.23 mmol) in 2 mL ofN,N-dimethyl-formamide was stirred at room temperature for 3 days.Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90,v/v to 90/10, v/v, over 10 min), gave the desired product (17 mg, 7.7%).LC-MS (m/z) 360.2 (M⁺).

Example 5 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1-methylpyrazol-5-yl)urea

[0119] a) 5-(azidocarbonyl)-1-methylpyrazole

[0120] To a solution of 1-methylpyrazol-5-carboxyhic acid (500 mg, 3.96mmol) in a mixture of acetone (6.6 mL) and water (3.3 mL) was addedtriethylamine (0.83 mL, 5.94 mmol). The mixture was cooled to 0° C. in aice-bath. Ethylchloroformate (774 mg, 7.13 mmol) was then added and theresulting mixture was stirred for 1.5 hours at 0° C. To the mixture wasadded sodium azide (0.52 g, 7.92 mmol), and the mixture was stirred foranother 2 hours. The mixture was concentrated, the residue was dilutedwith dichloromethane and washed with water. The organic layer was driedover MgSO₄ and concentrated to give desired product (280 mg, 47%). ¹HNMR(CDCl₃) (δ) 7.48 (s, 1H), 6.86 (s, 1H), 4.21 (s, 3H).

[0121] b)N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1-methylpyrazol-5-yl)urea

[0122] Under Ar, a solution of3-amino-6-chloro-2-hydroxybenzenesulfonamide (100 mg, 0.45 mmol) and5-(azidocarbonyl)-1-methylpyrazol (280 mg, 1.85 mmol) in 2 mL ofN,N-dimethyl-formamide was stirred at room temperature for 3 days.Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90,v/v to 90/10, v/v, over 10 min), gave the desired product (12 mg, 7.7%).LC-MS (m/z) 346.0 (M⁺).

Example 6 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-methyl-pyridin-3-yl)urea

[0123] a) 3-(azidocarbonyl)-2-methylpyridine

[0124] To a solution of 2-methylnicotinic acid (500 mg, 3.65 mmol) in amixture of acetone (6.6 mL) and water (3.3 mL) was added triethylamine(1.02 mL, 7.3 mmol). The mixture was cooled to 0° C. in a ice-bath.Ethylchloroformate (0.79 g, 7.3 mmol) was then added and the resultingmixture was stirred for 1.5 hours at 0° C. To the mixture was addedsodium azide (0.47 g, 7.3 mmol), and the mixture was stirred for another1.5 hours. The mixture was concentrated, the residue was diluted withdichloromethane and washed with water. The organic layer was dried overMgSO₄ and concentrated to give desired product (390 mg, 62%). ¹HNMR(CDCl₃) (δ) 8.67 (d, 1H), 8.21 (d, 1H), 7.24 (t, 1H), 2.88 (s, 3H).

[0125] b) N-(3-aminosulf671onyl-4-chloro-2-hydroxyphenyl)-N′-(2-methyl-pyridin-3-yl)urea

[0126] Under Ar, a solution of3-amino-6-chloro-2-hydroxybenzenesulfonamide (64 mg, 0.29 mmol) and3-(azidocarbonyl)-2-methylpyridine (390 mg, 2.41 mmol) in 1 mL ofN,N-dimethyl-formamide was stirred at room temperature for 20 hours.Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90,v/v to 90/10, v/v, over 10 min), gave the desired product (32 mg, 31%).LC-MS (m/z) 357.0 (M⁺).

Example 7 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(3,5-dimethylisoxazol-4-yl)urea

[0127] a)N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(3,5-dimethylisoxazol-4-yl)urea

[0128] Under Ar, a solution of3-amino-6-chloro-2-hydroxybenzenesulfonamide (50 mg, 0.23 mmol) and3,5-dimethylisoxazol4-yl isocyanate (31 mg, 0.23 mmol) in 1.0 mL ofN,N-dimethyl-formamide was stirred at room temperature for 20 hours.Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90,v/v to 90/10, v/v, over 10 min), gave the desired product (40 mg, 49%).LC-MS (m/z) 361.0 (M⁺).

Example 8 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(5-methylisoxazol-4-yl)urea

[0129] a) 4-(azidocarbonyl)-5-methylisooxazole

[0130] To a solution of 5-methylisoxazole-4-carboxylic acid (500 mg,3.94 mmol) in a mixture of acetone (10 mL) and water (3 mL) was addedtriethylamine (0.83 mL, 5.91 mmol). The mixture was cooled to 0° C. in aice-bath. Ethylchloroformate (640 mg, 5.91 mmol) was then added and theresulting mixture was stirred for 1.5 hours at 0° C. To the mixture wasadded sodium azide (410 mg, 6.30 mmol), and the mixture was stirred foranother 2 hours. The mixture was concentrated, the residue was dilutedwith dichloromethane and washed with water. The organic layer was driedover MgSO₄ and concentrated to give crude material, which was carried onto the coupling without further purification.

[0131] b)N-(3-anosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(5-methylisoxazol-4-yl)urea

[0132] Under Ar, a solution of3-amino-6-chloro-2-hydroxybenzenesulfonamide (238 mg, 1.07 mmol) and thecrude material of 4-(azidocarbonyl)-5-methylisooxazole in 5 mL ofN,N-dimethyl-formamide was stirred for 18 hours at room temperature.Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90,v/v to 90/10, v/v, over 10 min), gave the desired product (86 mg, 23%).LC-MS (m/z) 347.0 (M⁺).

Example 9 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hvdroxyphenyl)-N′-(3-methylisoxazol-4-yl)urea

[0133] a) N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(3-methylisoxazol-4-yl)urea

[0134] Under Ar, the mixture of 3-methylisoxazole-4-carboxylic acid (100mg, 0.79 mmol) in 2 mL of N,N-dimethyl-formamide was heated to 80° C.Diphenylphosphoryl azide (216 mg, 0.79 mmol) and triethyl amine (0.11mL, 0.79 mmol) were added. The resulting mixture was heated for another2 hours when kept temperature at 80° C. The mixture was cooled to roomtemperature, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide(176 mg, 0.79 mmol) in 1 mL of N,N-dimethyl-formamide then added. Themixture was stirred for 18 hours at room temperature. Purification uponGilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v,over 10 min), gave the desired product (43 mg, 16%). LC-MS (m/z) 347.0(M⁺).

Example 10 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(3-benzyloxythieno[2,3-b]pyridin-2-yl)urea

[0135] a)N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(3-benzyloxythieno[2,3-b]pyridin-2-yl)urea

[0136] Under Ar, the mixture of3-(benzyloxy)thieno[2,3-b]pyridine-2-carboxylic acid (150 mg, 0.53 mmol)in 2 mL of N,N-dimethyl-formamide was heated to 80° C.Diphenylphosphoryl azide (146 mg, 0.53 mmol),3-amino-6-chloro-2-hydroxybenzenesulfonamide (117 mg, 0.53 mmol) andtriethyl amine (0.054 mL, 0.53 mmol) were added. The resulting mixturewas heated for another 18 hours. when kept temperature at 70° C.Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90,v/v to 90/10, v/v, over 10 min), gave the desired product (70 mg, 26%).LC-MS (m/z) 505.2 (M⁺).

Example 11 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-chloro-1-N-oxide-pyridin-3-yl)urea

[0137] a)N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-chloro-1-N-oxide-pyridin-3-yl)urea

[0138] The mixture ofN-(3-aminosulfonyl4-chloro-2-hydroxyphenyl)-N′-(2-chloro-pyridin-3-yl)urea(50 mg, 0.13 mmol) and hydrogen peroxide (1.5 mL, 33 wt % solution inwater) in 5 mL of acetic acid was stirred for 18 hours at roomtemperature. Purification upon Gilson HPLC, eluting with acetonitrilelwater (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product(1.7 mg, 3%). LC-MS (m/z) 393.0 (M⁺).

Example 12 Preparation ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1-N-oxide-pyridin-2-yl)urea

[0139] The mixture ofN-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(pyridin-2-yl)urea (50mg, 0.13 mmol) and 3-chloroperoxybenzoic acid (189 mg, 0.62 mmol) in 5mL of acetone was stirred for, 1 hour at room temperature. Purificationupon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10,v/v, over 10 min), gave the desired product (11 mg, 7%). LC-MS (m/z)359.0 (M⁺).

METHOD OF TREATMENT

[0140] The compounds of Formula (I), or a pharmaceutically acceptablesalt thereof can be used in the manufacture of a medicine for theprophylactic or therapeutic treatment of any disease state in a human,or other mammal, which is exacerbated or caused by excessive orunregulated IL-8 cytokine production by such mammal's cell, such as butnot limited to monocytes and/or macrophages, or other chemokines whichbind to the IL-8 α or β receptor, also referred to as the type I or typeII receptor.

[0141] Accordingly, the present invention provides a method of treatinga chemokine mediated disease, wherein the chemokine is one which bindsto an IL-8 α or β receptor and which method comprises administering aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. In particular, the chemokines are IL-8, GROα,GROβ, GROγ, NAP-2 or ENA-78.

[0142] The compounds of Formula (I) are administered in an amountsufficient to inhibit cytokine function, in particular IL-8, GROα, GROβ,GROγ, NAP-2 or ENA-78, such that they are biologically regulated down tonormal levels of physiological function, or in some case to subnormallevels, so as to ameliorate the disease state. Abnormal levels of IL-8,GROα, GROβ, GROγ, NAP-2 or ENA-78 for instance in the context of thepresent invention, constitute: (i) levels of free IL-8 greater than orequal to 1 picogram per mL; (ii) any cell associated IIL-8, GROα, GROβ,GROγ, NAP-2 or ENA-78 above normal physiological levels; or (iii) thepresence of IL-8, GROα, GROβ, GROγ, NAP-2or ENA-78 above basal levels incells or tissues in which IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78respectively, is produced.

[0143] The compounds of Formula (I), in generally have been shown tohave a longer t_(½) and improved oral bioavailabilty over the compoundsdisclosed in WO 96/25157 and WO 97/29743 whose disclosures areincorporated herein by reference.

[0144] There are many disease states in which excessive or unregulatedIL-8 production is implicated in, exacerbating and/or causing thedisease. Chemokine mediated diseases include psoriasis, atopicdermatitis, osteo arthritis, rheumatoid arthritis, asthma, chronicobstructive pulmonary disease, adult respiratory distress syndrome,inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke,septic shock, multiple sclerosis, endotoxic shock, gram negative sepsis,toxic shock syndrome, cardiac and renal reperfusion injury,glomerulonephritis, thrombosis, graft vs. host reaction, Alzheimer'sdisease, allograft rejections, malaria, restenosis, angiogenesis,atherosclerosis, osteoporosis, gingivitis and undesired hematopoieticstem cells release and diseases caused by respiratory viruses, herpesviruses, and hepatitis viruses, meningitis, cystic fibrosis, pre-termlabor, cough, pruritus, multi-organ dysfunction, trauma, strains,sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNSvasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage,post surgical trauma, interstitial pneumonitis, hypersensitivity,crystal induced arthritis, acute and chronic pancreatitis, acutealcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis,uveitis, polymyositis, vasculitis, acne, gastric and duodenal ulcers,celiac disease, esophagitis, glossitis, airflow obstruction, airwayhyperresponsiveness, bronchiolitis obliterans organizing pneumonia,bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronicbronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea,hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia,surgerical lung volume reduction, pulmonary fibrosis, pulmonaryhypertension, right ventricular hypertropy, sarcoidosis, small airwaydisease, ventilation-perfusion mismatching, wheeze, colds and lupus.

[0145] These diseases are primarily characterized by massive neutrophilinfiltration, T-cell infiltration, or neovascular growth, and areassociated with increased IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78production which is responsible for the chemotaxis of neutrophils intothe inflammatory site or the directional growth of endothelial cells. Incontrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8,GROα, GROβ, GROγ, NAP-2 or ENA-78 have the unique property of promotingneutrophil chemotaxis, enzyme release including but not limited toelastase release as well as superoxide production and activation. Theα-chemokines but particularly, GROα, GROβ, GROγ, NAP-2 or ENA-78,working through the IL-8 type I or II receptor can promote theneovascularization of tumors by promoting the directional growth ofendothelial cells. Therefore, the inhibition of IL-8 induced chemotaxisor activation would lead to a direct reduction in the neutrophilinfiltration.

[0146] Recent evidence also implicates the role of chemokines in thetreatment of HIV infections, Littleman et al., Nature 381, pp. 661(1996) and Koup et al., Nature 381, pp. 667 (1996).

[0147] Present evidence also indicates the use of IL-8 inhibitors in thetreatment of atherosclerosis. The first reference, Boisvert et al., J.Clin. Invest, 1998, 101:353-363 shows, through bone marrowtransplantation, that the absence of IL-8 receptors on stem cells (and,therefore, on monocytes/macrophages) leads to a reduction in thedevelopment of atherosclerotic plaques in LDL receptor deficient mice.Additional supporting references are: Apostolopoulos, et al.,Arterioscler. Thromb. Vase. Biol. 1996, 16:1007-1012; Liu, et al.,Arterioscler. Thromb. Vasc. Biol, 1997, 17:317-323; Rus, et al.,Atherosclerosis. 1996, 127:263-271.; Wang et al., J. Biol. Chem. 1996,271:8837-8842; Yue, et al., Eur. J. Pharnacol. 1993, 240:81-84; Koch, etal., Am. J. Pathol., 1993, 142:1423-1431.; Lee, et al., Immunol. Lett.,1996, 53, 109-113.; and Terkeltaub et al., Arterioscler. Thromb., 1994,14:47-53.

[0148] The present invention also provides for a means of treating, inan acute setting, as well as preventing, in those individuals deemedsusceptible to, CNS injuries by the chemokine receptor antagonistcompounds of Formula (I).

[0149] CNS injuries as defined herein include both open or penetratinghead trauma, such as by surgery, or a closed head trauma injury, such asby an injury to the head region. Also included within this definition isischemic stroke, particularly to the brain area.

[0150] Ischemic stroke may be defined as a focal neurologic disorderthat results from insufficient blood supply to a particular brain area,usually as a consequence of an embolus, thrombi, or local atheromatousclosure of the blood vessel. The role of inflammatory cytokines in thisarea has been emerging and the present invention provides a mean for thepotential treatment of these injuries. Relatively little treatment, foran acute injury such as these has been available.

[0151] TNF-α is a cytokine with proinflammatory actions, includingendothelial leukocyte adhesion molecule expression. Leukocytesinfiltrate into ischemic brain lesions and hence compounds which inhibitor decrease levels of TNF would be useful for treatment of ischemicbrain injury. See Liu et al., Stroke, Vol. 25., No. 7, pp. 1481-88(1994) whose disclosure is incorporated herein by reference.

[0152] Models of closed head injuries and treatment with mixed 5-LO/COagents is discussed in Shohami et al., J. of Vaisc & Clinical Physiologyand Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992) whose disclosure isincorporated herein by reference. Treatment, which reduced edemaformation, was found to improve functional outcome in those animalstreated.

[0153] The compounds of Formula (I) are administered in an amountsufficient to inhibit IL-8, binding to the IL-8 alpha or beta receptors,from binding to these receptors, such as evidenced by a reduction inneutrophil chemotaxis and activation. The discovery that the compoundsof Formula (I) are inhibitors of IL-8 binding is based upon the effectsof the compounds of Formulas (I) in the in vitro receptor binding assayswhich are described herein. The compounds of Formula (I) have been shownto be inhibitors of type II IL-8 receptors.

[0154] As used herein, the term “IL-8 mediated disease or disease state”refers to any and all disease states in which IL-8, GROα, GROβ, GROγ,NAP-2 or ENA-78 plays a role, either by production of IL-8, GROα, GROβ,GROγ, NAP-2 or ENA-78 themselves, or by IL-8, GROα, GROβ, GROγ, NAP-2 orENA-78 causing another monokine to be released, such as but not limitedto IL-1, IL-6 or TNF. A disease state in which, for instance, IL-1 is amajor component, and whose production or action, is exacerbated orsecreted in response to IL-8, would therefore be considered a diseasestate mediated by IL-8.

[0155] As used herein, the term “chemokine mediated disease or diseasestate” refers to any and all disease states in which a chemokine whichbinds to an IL-8 α or β receptor plays a role, such as but not limitedto IL-8, GRO-α, GRO-β, GROγ, NAP-2 or ENA-78. This would include adisease state in which, IL-8 plays a role, either by production of IL-8itself, or by IL-8 causing another monokine to be released, such as butnot limited to IL-1, IL-6 or TNF. A disease state in which, forinstance, IL-1 is a major component, and whose production or action, isexacerbated or secreted in response to IL-8, would therefore beconsidered a disease stated mediated by IL-8.

[0156] As used herein, the term “cytokine” refers to any secretedpolypeptide that affects the functions of cells and is a molecule, whichmodulates interactions between cells in the immune, inflammatory orhematopoietic response. A cytokine includes, but is not limited to,monokines and lymphokines, regardless of which cells produce them. Forinstance, a monokine is generally referred to as being produced andsecreted by a mononuclear cell, such as a macrophage and/or monocyte.Many other cells however also produce monokines, such as natural killercells, fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta(TNF-β).

[0157] As used herein, the term “chemokine” refers to any secretedpolypeptide that affects the flnctions of cells and is a molecule whichmodulates interactions between cells in the immune, inflammatory orhematopoietic response, similar to the term “cytokine” above. Achemokine is primarily secreted through cell transmembranes and causeschernotaxis and activation of specific white blood cells and leukocytes,neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cellsand smooth muscle cells. Examples of chemokines include, but are notlimited to IL-8, GRO-α, GRO-β, GRO-γ, NAP-2, ENA-78, IP-10, MIP-1α,MIP-β, PF4, and MCP 1, 2, and 3.

[0158] In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound ofFormula (I) and a pharmaceutically acceptable carrier or diluent.

[0159] Compounds of Formula (I), pharmaceutically acceptable saltsthereof and pharmaceutical compositions incorporating such mayconveniently be administered by any of the routes conventionally usedfor drug administration, for instance, orally, topically, parenterallyor by inhalation. The compounds of Formula (I) may be administered inconventional dosage forms prepared by combining a compound of Formula(I) with standard pharmaceutical carriers according to conventionalprocedures. The compounds of Formula (I) may also be administered inconventional dosages in combination with a known, second therapeuticallyactive compound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

[0160] The pharmaceutical carrier employed may be, for example, either asolid or liquid. Exemplary of solid carriers are lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like. Similarly, the carrier ordiluent may include time delay material well known to the art, such asglyceryl mono-stearate or glyceryl distearate alone or with a wax.

[0161] A wide variety of pharmaceutical forms can be employed. Thus, ifa solid carrier is used, the preparation can be tableted, placed in ahard gelatin capsule in powder or pellet form or in the form of a trocheor lozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

[0162] Compounds of Formula (I) may be administered topically, that isby non-systemic administration. This includes the application of acompound of Formula (I) externally to the epidermis or the buccal cavityand the instillation of such a compound into the ear, eye and nose, suchthat the compound does not significantly enter the blood stream. Incontrast, systemic administration refers to oral, intravenous,intraperitoneal and intramuscular administration.

[0163] Formulations suitable for topical administration include liquidor semi-iquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theFormulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe Formulation.

[0164] Lotions according to the present invention include those suitablefor application to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

[0165] Creams, ointments or pastes according to the present inventionare semi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient in finelydivided or powdered form, alone or in solution or suspension in anaqueous or non-aqueous fluid, with the aid of suitable machinery, with agreasy or non-greasy base. The base may comprise hydrocarbons such ashard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; amucilage; an oil of natural origin such as almond, corn, arachis, castoror olive oil; wool fat or its derivatives or a fatty acid such as stericor oleic acid together with an alcohol such as propylene glycol or amacrogel. The formulation may incorporate any suitable surface activeagent such as an anionic, cationic or non-ionic surfactant such as asorbitan ester or a polyoxyethylene derivative thereof. Suspendingagents such as natural gums, cellulose derivatives or inorganicmaterials such as silicaceous silicas, and other ingredients such aslanolin, may also be included.

[0166] Drops according to the present invention may comprise sterileaqueous or oily solutions or suspensions and may be prepared bydissolving the active ingredient in a suitable aqueous solution of abactericidal and/or fungicidal agent and/or any other suitablepreservative, and preferably including a surface active agent. Theresulting solution may then be clarified by filtration, transferred to asuitable container, which is then sealed and sterilized by autoclaving,or maintaining at 98-100° C. for half an hour. Alternatively, thesolution may be sterilized by filtration and transferred to thecontainer by an aseptic technique. Examples of bactericidal andfungicidal agents suitable for inclusion in the drops are phenylmercuricnitrate or acetate (0.002%), benzalkonium chloride (0.01%) andchlorhexidine acetate (0.01%). Suitable solvents for the preparation ofan oily solution include glycerol, diluted alcohol and propylene glycol.

[0167] Compounds of formula (I) may be administered parenterally, thatis by intravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parenteral administration are generallypreferred. Appropriate dosage forms for such administration may beprepared by conventional techniques. Compounds of Formula (I) may alsobe administered by inhalation that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

[0168] For all methods of use disclosed herein for the compounds ofFormula (I) the daily oral dosage regimen will preferably be from about0.01 to about 80 mg/kg of total body weight. The daily parenteral dosageregimen about 0.001 to about 80 mg/kg of total body weight. The dailytopical dosage regimen will preferably be from 0.1 mg to 150 mg,administered one to four, preferably two or three times daily. The dailyinhalation dosage regimen will preferably be from about 0.01 mg/kg toabout 1 mg/kg per day. It will also be recognized by one of skill in theart that the optimal quantity and spacing of individual dosages of acompound of Formula (I) or a pharmaceutically acceptable salt thereofwill be determined by the nature and extent of the condition beingtreated, the form, route and site of administration, and the particularpatient being treated, and that such optimums can be determined byconventional techniques. It will also be appreciated by one of skill inthe art that the optimal course of treatment, i.e., the number of dosesof a compound of Formula (I) or a pharmaceutically acceptable saltthereof given per day for a defined number of days, can be ascertainedby those skilled in the art using conventional course of treatmentdetermination tests.

[0169] The invention will now be described by reference to the followingbiological examples, which are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

BIOLOGICAL EXAMPLES

[0170] The IL-8, and GRO-α chemokine inhibitory effects of compounds ofthe present invention are determined by the following in vitro assay.

[0171] Receptor Binding Assays:

[0172] [¹²⁵I] IL-8 (human recombinant) is obtained from Amersham Corp.,Arlington Heights, Ill., with specific activity 2000 Ci/mmol. GRO-α isobtained from NEN—New England Nuclear. All other chemicals are ofanalytical grade. High levels of recombinant human IL-8 type α and βreceptors were individually expressed in Chinese hamster ovary cells asdescribed previously (Holmes, et al., Science, 1991, 253, 1278). TheChinese hamster ovary membranes were homogenized according to apreviously described protocol (Haour, et al., J. Biol. Chem., 249 pp2195-2205 (1974)). Except that the homogenization buffer is changed to10 mM Tris-HCL, 1 mM MgSO₄, 0.5 mM EDTA (ethylene-diaminetetra-aceticacid), 1 mM PMSF (to-toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH7.5. Membrane protein concentration is determined using Pierce Co.micro-assay kit using bovine serum albumin as a standard. All assays areperformed in a 96-well micro plate format. Each reaction mixturecontains ¹²⁵I IL-8 (0.25 nM) or ¹²⁵I GRO-α and 0.5 μg/mL of IL-8Rα or1.0 μg/mL of IL-8Rβ membranes in 20 mM Bis-Trispropane and 0.4 mM TrisHCl buffers, pH 8.0, containing 1.2 mM MgSO₄, 0.1 mM EDTA, 25 mM Na and0.03% CHAPS. In addition, drug or compound of interest is added whichhas been pre-dissolved in DMSO so as to reach a final concentration ofbetween 0.01 nM and 100 uM. The assay is initiated by addition of¹²⁵I-IL-8. After 1 hour at room temperature the plate is harvested usinga Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1%polyethylenimine/0.5% BSA and washed 3 times with 25 mM NaCl, 10 mMTrisHCl, 1 MM MgSO₄, 0.5 mM EDTA, 0.03% CHAPS, pH 7.4. The filter isthen dried and counted on the Betaplate liquid scintillation counter.The recombinant IL-8 Rα, or Type I, receptor is also referred to hereinas the non-permissive receptor and the recombinant IL-8 is Rβ, or TypeII, receptor is referred to as the permissive receptor.

[0173] Representative compounds of Formula (I), Examples 1 to 106 haveexhibited positive inhibitory activity in this assay at IC₅₀ levels <30uM.

[0174] Chemotaxis Assay:

[0175] The in vitro inhibitory properties of these compounds aredetermined in the neutrophil chemotaxis assay as described in CurrentProtocols in Immunology, vol. I, Suppl 1, Unit 6.12.3., whose disclosureis incorporated herein by reference in its entirety. Neutrophils whereisolated from human blood as described in Current Protocols inImmunology Vol. I, Suppl 1 Unit 7.23.1, whose disclosure is incorporatedherein by reference in its entirety. The chemoattractants IL-8, GRO-α,GRO-β, GRO-γ and NAP-2 are placed in the bottom chamber of a 48multiwell chamber (Neuro Probe, Cabin John, Md.) at a concentrationbetween 0.1 and 100 nM. The two chambers are separated by a 5 uMpolycarbonate filter. When compounds of this invention are tested, theyare mixed with the cells (0.001-1000 nM) just prior to the addition ofthe cells to the upper chamber. Incubation is allowed to proceed forbetween about 45 and 90 min at about 37° C. in a humidified incubatorwith 5% CO₂. At the end of the incubation period, the polycarbonatemembrane is removed and the topside washed, the membrane then stainedusing the Diff Quick staining protocol (Baxter Products, McGaw Park,Ill., USA). Cells which have chemotaxed to the chemokine are visuallycounted using a microscope. Generally, four fields are counted for eachsample, these numbers are averaged to give the average number of cellswhich had migrated. Each sample is tested in triplicate and eachcompound repeated at least four times. To certain cells (positivecontrol cells) no compound is added, these cells represent the maximumchemotactic response of the cells. In the case where a negative control(unstimulated) is desired, no chemokine is added to the bottom chamber.The difference between the positive control and the negative controlrepresents the chemotactic activity of the cells.

[0176] Elastase Release Assay:

[0177] The compounds of this invention are tested for their ability toprevent Elastase release from human neutrophils. Neutrophils areisolated from human blood as described in Current Protocols inImmunology Vol. I, Suppl 1 Unit 7.23.1. PMNs 0.88×10⁶ cells suspended inRinger's Solution (NaCl 118, KCl 4.56, NaHCO₃ 25, KH₂PO₄ 1.03, Glucose11.1, HEPES 5 mM, pH 7.4) are placed in each well of a 96 well plate ina volume of 50 ul. To this plate is added the test compound (0.001-1000nM) in a volume of 50 ul, Cytochalasin B in a volume of 50 ul (20 ug/ml)and Ringers buffer in a volume of 50 ul. These cells are allowed to warm(37° C., 5% CO2, 95% RH) for 5 min before IL-8, GROα, GROβ, GROγ orNAP-2 at a final concentration of 0.01-1000 nM was added. The reactionis allowed to proceed for 45 min before the 96 well plate is centrifuged(800×g 5 min.) and 100 ul of the supernatant removed. This supernatantis added to a second 96 well plate followed by an artificial elastasesubstrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, Calif.)to a final-concentration of 6 ug/ml dissolved in phosphate bufferedsaline. Immediately, the plate is placed in a fluorescent 96 well platereader (Cytofluor 2350, Millipore, Bedford, Mass.) and data collected at3 min intervals according to the method of Nakajima et al J. Biol. Chem.254 4027 (1979). The amount of Elastase released from the PMNs iscalculated by measuring the rate of MeOSuc-Ala-Ala-Pro-Val-AMCdegradation.

[0178] TNF-α in Traumatic Brain Injury Assay:

[0179] The present assay provides for examination of the expression oftumor necrosis factor mRNA in specific brain regions, which followexperimentally, induced lateral fluid-percussion traumatic brain injury(TBI) in rats. Adult Sprague-Dawley rats (n=42) were anesthetized withsodium pentobarbital (60 mg/kg, i.p.) and subjected to lateralfluid-percussion brain injury of moderate severity (2.4 atm.) centeredover the left temporaparietal cortex (n=18), or “sham” treatment(anesthesia and surgery without injury, n=18). Animals are sacrificed bydecapitation at 1, 6 and 24 hr. post injury, brains removed, and tissuesamples of left (injured) parietal cortex (LC), corresponding area inthe contralateral right cortex (RC), cortex adjacent to injured parietalcortex (LA), corresponding adjacent area in the right cortex (RA), lefthippocampus (LH) and right hippocampus (RH) are prepared. Total RNA areisolated and Northern blot hybridization is performed and quantitatedrelative to an TNF-α positive control RNA (macrophage=100%). A markedincrease of TNF-α mRNA expression is observed in LH (104±17% of positivecontrol, p<0.05 compared with sham), LC (105±21%, p<0.05) and LA (69±8%,p<0.01) in the traumatized hemisphere 1 hr. following injury. Anincreased TNF-α mRNA expression is also observed in LH (46±8%, p<0.05),LC (30±3%, p<0.01) and LA (32±3%, p<0.01) at 6 hr which resolves by 24hr following injury. In the contralateral hemisphere, expression ofTNF-α mRNA is increased in RH (46±2%, p<0.01), RC (4±3%) and RA (22±8%)at 1 hr and in RH (28±11%), RC (7±5%) and RA (26±6%, p<0.05) at 6 hr butnot at 24 hr following injury. In sham (surgery without injury) or naiveanimals, no consistent changes in expression of TNF-α mRNA are observedin any of the 6 brain areas in either hemisphere at any times. Theseresults indicate that following parasagittal fluid-percussion braininjury, the temporal expression of TNF-α mRNA is altered in specificbrain regions, including those of the non-traumatized hemisphere. SinceTNF-α is able to induce nerve growth factor (NGF) and stimulate therelease of other cytokines from activated astrocytes, thispost-traumatic alteration in gene expression of TNF-α plays an importantrole in both the acute and regenerative response to CNS trauma.

[0180] CNS Injury model for IL-1β mRNA:

[0181] This assay characterizes the regional expression ofinterleukin-1β (IL-1β) mRNA in specific brain regions followingexperimental lateral fluid-percussion traumatic brain injury (TBI) inrats. Adult Sprague-Dawley rats (n=42) are anesthetized with sodiumpentobarbital (60 mg/kg, i.p.) and subjected to lateral fluid-percussionbrain injury of moderate severity (2.4 atm.) centered over the lefttemporaparietal cortex (n=18), or “sham” treatment (anesthesia andsurgery without injury). Animals are sacrificed at 1, 6 and 24 hr. postinjury, brains removed, and tissue samples of left (injured) parietalcortex (LC), corresponding area in the contralateral right cortex (RC),cortex adjacent to injured parietal cortex (LA), corresponding adjacentarea in the right cortex (RA), left hippocampus (LH) and righthippocampus (RH) are prepared. Total RNA is isolated and Northern blothybridization was performed and the quantity of brain tissue IL-1β mRNAis presented as percent relative radioactivity of IL-1β positivemacrophage RNA which was loaded on the same gel. At 1 hr following braininjury, a marked and significant increase in expression of IL-1β mRNA isobserved in LC (20.0±0.7% of positive control, n=6, p<0.05 compared withsham animal), LH (24.5±0.9%, p<0.05) and LA (21.5±3.1%, p<0.05) in theinjured hemisphere, which remained elevated up to 6 hr. post injury inthe LC (4.0±0.4%, n=6, p<0.05) and LH (5.0±1.3%, p<0.05). In sham ornaive animals, no expression of IL-1β mRNA is observed in any of therespective brain areas. These results indicate that following TBI, thetemporal expression of IL-1β mRNA is regionally stimulated in specificbrain regions. These regional changes in cytokines, such as IL-1β play arole in the post-traumatic.

[0182] All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

[0183] The above description fully discloses the invention includingpreferred embodiments thereof. Modifications and improvements of theembodiments specifically disclosed herein are within the scope of thefollowing claims. Without further elaboration, it is believed that oneskilled in the art can, using the preceding description, utilize thepresent invention to its fullest extent. Therefore the Examples hereinare to be construed as merely illustrative and not a limitation of thescope of the present invention in any way. The embodiments of theinvention in which an exclusive property or privilege is claimed aredefined as follows.

What is claimed is:
 1. A compound of the formula (I):

wherein R_(b) is independently selected from the group consisting of hydrogen, NR₆R₇, OH, OR_(a), C₁₋₅alkyl, aryl, arylC₁₋₄alkyl, aryl C₂₋₄alkenyl, cycloalkyl, cycloalkyl C₁₋₅ alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, heterocyclic C₁₋₄alkyl, and a heterocyclic C₂₋₄alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by a substituent selected from the group consisting of halogen, nitro, halosubstituted C₁₋₄ alkyl, C₁₋₄ alkyl, amino, mono or di-C₁₋₄ alkyl substituted amine, OR_(a),C(O)R_(a),NR_(a)C(O)OR_(a), OC(O)NR₆R₇, hydroxy, NR₉C(O)R_(a), S(O)_(m′)R_(a), C(O)NR₆R₇, C(O)OH, C(O)OR_(a), S(O)₂NR₆R₇ and NHS(O)₂R_(a); or the two R_(b) substituents join to form a 3-10 membered ring, optionally substituted and containing, in addition to carbon, independently, 1 to 3 optionally substituted moieties selected from the group consisting of NR_(a), O, S, SO, and SO₂; R_(a) is selected from the group consisting of alkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroaryl C₁₋₄alkyl, heterocyclic, COOR_(a), and a heterocyclic C₁₋₄alkyl moiety, all of which moieties may be optionally substituted; m is an integer having a value of 1 to 3; m′ is 0, or an integer having a value of 1 or 2; n is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; t is 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; R₁ is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, C₁₋₁₀ alkyl, halosubstituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkoxy, halosubstituted C₁₋₁₀alkoxy, azide, S(O)_(t)R₄, (CR₈R₈)_(q) S(O)_(t)R₄, hydroxy, hydroxy substituted C₁₋₄alkyl, aryl, aryl C₁₋₄ alkyl, aryl C₂-₁₀ alkenyl, aryloxy, aryl C₁₋₄ alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C₂₋₁₀ alkenyl, heteroaryl C₁₋₄ alkyloxy, heterocyclic, heterocyclic C₁₋₄alkyl, heterocyclicC₁₋₄alkyloxy, heterocyclicC₂₋₁₀ alkenyl, (CR₈R₈)_(q) NR₄R₅, (CR₈R₈)_(q)C(O)NR₄R₅, C₂₋₁₀ alkenyl C(O)NR₄R₅, (CR₈R₈)_(q) C(O)NR₄R₁₀, S(O)₃R₈, (CR₈R₈)_(q) C(O)R₁₁, C₂₋₁₀ alkenyl C(O)R₁₁, C₂₋₁₀ alkenyl C(O)OR₁₁, (CR₈R₈)_(q) C(O)OR₁₁, (CR₈R₈)_(q) OC(O)R₁₁, (CR₈R₈)_(q)NR₄C(O)R₁₁, (CR₈R₈)_(q) C(NR₄)NR₄R₅, (CR₈R₈)q NR₄C(NR₅)R₁₁, (CR₈R₈)_(q) NHS(O)₂R₁₃, and (CR₈R₈)_(q) S(O)₂NR₄R₅; or two R₁ moieties together may form O—(CH₂)_(s)O or a 5 to 6 membered saturated or unsaturated ring, such that the alkyl, aryl, arylalkyl, heteroaryl, or heterocyclic moieties may be optionally substituted; R₄ and R₅ are independently selected form the group consisting of hydrogen, optionally substituted C₁₋₄ alkyl, optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C₁₋₄alkyl, heterocyclic, and heterocyclicC₁₋₄ alkyl, or R₄ and R₅ together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N and S; R₆ and R₇ are independently selected from the group consisting of hydrogen, a C₁₋₄ alkyl, heteroaryl, aryl, aklyl aryl, and alkyl C₁₋₄ heteroalkyl; or R₆ and R₇ together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which is selected from the group consisting of oxygen, nitrogen or sulfur, and which ring may be optionally substituted; Y is selected from the group consisting of furan, thiophene, pyrrole, oxazole, imidazole, thiazole, thieno(2,3 b)pyridine, pyrazole, isooxazole, isothiazole, 1,2,3 or 1,2,4 oxadiazole, 1,2,3 or 1,2,4 triazole, 1,2,3 or 1,2,4 thiadiazole, pyridine, pyridine-N-oxide, pyrimidine, pyridazine, pyrazine, 1,3,5, or 1,2,3 or 1,2,4 triazine, 1,2,4,5 tetrazine, indole, benzofuran, indazole, benzimidazole, benzothiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline all of which moeities can be substituted 1-3 times with R₁ R₈ is hydrogen or C₁₋₄ alkyl; R₉ is hydrogen or a C₁₋₄ alkyl; R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈; R₁₁ is selected from the group consisting of hydrogen, optionally substituted C₁₋₄ alkyl, optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC₁₋₄alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclicC₁₋₄alkyl; and R₁₃ is selected from the group consisting of C₁₋₄ alkyl, aryl, aryl C₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclic, and heterocyclicC₁₋₄alkyl; or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1 wherein R₁ is substituted in the 4- position by an electron withdrawing moiety.
 3. The compound according to claim 2 wherein R₁ is halogen, methyl, cyano or nitro.
 4. The compound according to claim 3 wherein R₁ is halogen.
 5. The compound according to claim 4 wherein R₁ is independently, fluorine, chlorine, or bromine.
 6. The compound according to claim 1 wherein Y is mono-substituted in the 2′-position or 3′- position, or is disubstituted in the 2′- or 3′- position of a monocyclic ring.
 7. The compound according to claim 6 wherein Y is pyridine and pyrazole.
 8. The compound according to claim 1 wherein R_(b) is hydrogen, C₁₋₄ alkyl, or C₁₋₄ alkyl substituted with C(O)OH, or C(O)OR_(a).
 9. The compound according to claim 1 which is: N-(3-aminosulfonyl4-chloro-2-hydroxyphenyl)-N′-(pyridin-2-yl)urea; N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-chloro-pyridin-3-yl)urea; N-(3-aminosulfonyl4-chloro-2-hydroxyphenyl)-N′-(1-phenyl-1H-1,2,3-triazol-5-yl)urea; N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1,3-dimethylpyrazol-5-yl)urea; N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(1-methylpyrazol-5-yl)urea; and N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-methyl-pyridin-3-yl)urea N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(3,5-dimethylisoxazol-4-yl)urea N-(3-aminosulfonyl4-chloro-2-hydroxyphenyl)-N′-(1-N-oxide-pyridin-3-yl)urea N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(2-chloro-1-N-oxide-pyridin-3-yl)urea N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(3-benzyloxythieno[2,3-b]pyridin-2-yl)urea N-(3-aminosulfonyl4-chloro-2-hydroxyphenyl)-N′-(3-methylisoxazol-4-yl)urea N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-N′-(5-methylisoxazol-4-yl)urea.
 10. A compound according to claim 9 wherein the compound is in its sodium salt form.
 11. A compound according to claim 10 wherein the compound is in its potassium salt form.
 12. A pharmaceutical composition comprising a compound according to any of claims 1 to 11 and a pharmaceutically acceptable carrier or diluent.
 13. A method of treating a chemokine mediated disease, wherein the chemokine binds to an IL-8 a or b receptor in a mammal, which method comprises administering to said mammal an effective amount of a compound of the formula according to any one of claims 1 to
 11. 14. The method according to claim 13 wherein the mammal is afflicted with a chemokine mediated disease selected from the group consisting of: psoriasis, atopic dermatitis, osteo arthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, multiple sclerosis, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, Alzheimer's disease, allograft rejections, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis and undesired hematopoietic stem cells release and diseases caused by respiratory viruses, herpes viruses, and hepatitis viruses, meningitis, cystic fibrosis, pre-term labor, cough, pruritus, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiolitis obliterans organizing pneumonia, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgerical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertropy, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds and lupus. 